Scientists with Ludwig Cancer Research say they have discovered a mechanism that shows the reason behind many cancer cells’ dependency on the amino acid methionine. The team believes its work could lead to new ways to treat a number of breast tumors.

“Most normal cells generally can survive the acute deprivation of methionine, but some tumor cells are very sensitive to its scarcity,” says Alex Toker, Ph.D., an investigator at the Ludwig Center at Harvard Medical School. “…we show how this methionine dependency is controlled by PIK3CA, a gene that drives cancer when it is mutated in a way that hyperactivates its protein product.”

Dr. Toker and his colleagues report in their paper (“Oncogenic PI3K Promotes Methionine Dependency in Breast Cancer Cells through the Cystine-Glutamate Antiporter xCT”), which appears in Science Signaling, that the oncogenic PIK3CA's abnormal activity alters the cell's production of methionine by inhibiting the activity of another protein named xCT, which imports a molecule involved in the cell's production of a related amino acid.

“We showed that oncogenic PIK3CA and decreased expression of SLC7A11, a gene that encodes a cystine transporter also known as xCT, correlated with increased methionine dependency in breast cancer cells. Oncogenic PIK3CA was sufficient to confer methionine dependency to mammary epithelial cells, partly by decreasing cystine uptake through the transcriptional and posttranslational inhibition of xCT. Manipulation of xCT activity altered the proliferation of breast cancer cells in methionine-deficient, homocysteine-containing media, suggesting that it functionally contributed to methionine dependency,” write the investigators.

“We propose that concurrent with decreased cystine uptake through xCT, PIK3CA mutant cells use homocysteine through the transsulfuration pathway to synthesize cysteine. Consequently, less homocysteine is available to produce methionine, contributing to methionine dependency. These results indicate that oncogenic PIK3CA alters methionine and cysteine utilization, partly by inhibiting xCT to contribute to the methionine dependency phenotype in breast cancer cells.”

“The concept that all cancers rewire metabolic pathways to fuel the needs of rapidly dividing cells has gained great traction in the cancer community in the last decade or so,” Dr. Toker said. “We and many other labs have been trying to drill deep in identifying such metabolic vulnerabilities to arrive at novel therapeutic approaches to treating patients.”

In their study, Dr. Toker's team screened 13 breast cancer lines to identify those that are unable to survive in methionine-starved environments. When a closer look found that most of these Met-dependent cancer cells also carried mutations in the PIK3CA gene, the scientists hypothesized that the oncogenic PIK3CA might be altering processes involved in methionine metabolism. A review of the published literature revealed that Met dependency in cancer cells is often correlated with low levels of xCT activity.

The scientists speculated that in cancer cells where oncogenic PIK3CA is blocking cystine import, homocysteine would be used to make cysteine. This would leave less homocysteine available to produce methionine, making those breast cancer cells more dependent on an external supply of methionine. To accomplish that, Dr. Toker and his team used an existing drug called sulfasalazine that is known to inhibit xCT. 

When treated with sulfasalazine, breast cancer cells that would normally survive in methionine-starved environments were no longer able to do so. In effect, the drug made the cells methionine-dependent by mimicking the effects of a mutant PIK3CA gene.

The study raises the possibility of killing tumors by triggering methionine dependency using sulfasalazine or other drugs, explained Dr. Toker.

“The idea would be to target tumors with a drug that blocks xCT,” he said. “By doing this, a tumor cell would push homocysteine toward cysteine biosynthesis and the cell would ultimately die due to methionine deprivation, while leaving normal cells unaffected.”